Mechanisms of Glial Development in C. elegans

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2021

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Glia make up roughly half of all cells in the mammalian nervous system and play a major part in nervous system development, function and disease. Although research in the past few decades have shed light on their morphological and functional diversity, there is still much to be known about key aspects of their development such as the generation of glial diversity and the factors governing proper morphogenesis. In the work presented here I started with a forward genetic screen using amphid sheath (AMsh) glia in the model organism C. elegans and uncovered various factors that govern different aspects of glial development including glial fate specification, migration and growth. First, I identified the function of the proneural gene lin-32/Atoh1 in repressing an AMsh glial fate. Gliogenesis is a fundamental process during nervous system development, and generating the appropriate number of specific glial cell types is required for proper nervous system function. lin-32 loss of function mutants possess additional AMsh glia beyond the normal pair. Interestingly, the ectopic AMsh cells at least partially arise from cells originally fated to become CEPsh glia, suggesting that lin-32 may be involved in the specification of specific glial subtypes. I also found that lin-32 acts in parallel with two other proneural transcription factors cnd-1/NeuroD1 and ngn-1/Neurog1 in negatively regulating an AMsh glia fate. Furthermore, expression of murine Atoh1 fully rescues lin-32 mutant phenotypes, suggesting potential functional conservation during glial fate specification. Next, I found that AMsh glial migration is regulated by vitamin B12 through isoform-specific expression of PTP-3/LAR PTPR (Leukocyte-common antigen related receptor-type tyrosine-protein phosphatase). The uptake of diet-supplied vitamin B12 in the intestine was found to be critical for the expression of a long isoform of PTP-3 (PTP-3A) in neuronal and glial cells. The expression of PTP-3A then cell-autonomously regulates glial migration and synapse formation through interaction with an extracellular matrix protein NID-1/Nidogen 1. Together, my findings demonstrate that isoform-specific regulation of PTP-3/LAR PTPR expression mediates vitamin B12-dependent neuronal and glial development. These results may also help inform our understanding of neurodevelopmental and degenerative disorders linked to vitamin B12 deficiency. Finally I identified a pathway that regulates AMsh cell growth involving the conserved cis Golgi membrane protein eas-1/GOLT1B. Coordination of cell growth is essential for the development of the brain, but the molecular mechanisms underlying the regulation of glial size are poorly understood. My research shows that that eas-1 inhibits a conserved E3 ubiquitin ligase rnf-145/RNF145, which in turn promotes nuclear activation of sbp-1/ SREBP, an important regulator of sterol and fatty acid synthesis, to restrict cell growth. At early developmental stages, rnf-145 in the cis Golgi network inhibits sbp-1 activation to promote the growth of glia, and when animals reach the adult stage this inhibition is released through an eas-1-dependent shuttling of rnf-145 from the cis Golgi to the trans Golgi network to stop glial growth. Furthermore, I identified long chain polyunsaturated fatty acids (LC-PUFAs), especially eicosapentaenoic acid (EPA), as downstream products of the eas-1-rnf-145-sbp-1 pathway that functions to prevent the overgrowth of glia. These findings reveal a novel and potentially conserved mechanism underlying glial size control. Taken together, my research reveals several pathways that regulate different stages of AMsh glial development. Since many of these pathways are conserved, study of C. elegans glial development may also help inform our understanding of glial biology in vertebrate systems.

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Zhang, Albert (2021). Mechanisms of Glial Development in C. elegans. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/22956.

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